The present invention relates to antibiotic compounds and in particularto antibiotic compounds containing a furanone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium.
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycii. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventors have discovered a class of antibiotic compounds containing a furanone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both amninoglycosides and clinically used xcex2-lactams.
We have now discovered a range of compounds that is not suggested by the art and which has good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (for example Walter A. Gregory et al in J.Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly, there is provided a compound of the formula (I): 
wherein:
R1 is hydroxy or of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl or xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2;
R2 and R3 are independently hydrogen or fluoro;
R4and R5 are independently hydrogen or methyl;
 greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94,  greater than CHCH2xe2x80x94 or  greater than C(OH)CH2xe2x80x94 ( greater than  represents two single bonds);
D is O, S, SO, SO2or NR7;
R7 is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, AR (as defined hereinbelow) or a tetrazole ring system (optionally mono-substituted in the 1- or 2-position of the tetrazole ring) wherein the tetrazole ring system is joined to the nitrogen in NR7 by a ring carbon atom;
or R7 is of the formula R10COxe2x80x94, R10SO2xe2x80x94 or R10CSxe2x80x94
wherein R10 is AR (as defined hereinbelow), cyclopentyl or cyclohexyl (wherein the last two-mentioned cycloalkyl rings are optionally mono- or disubstituted by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano and trifluoromethyl), (1-4C)alkoxycarbonyl, hydrogen, amino, trifluoromethyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, 2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin6-yl, 2-(2-furyl)ethenyl, 2-(2-thienyl)ethenyl, 2-phenylethenyl (wherein the phenyl substituent is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), 3,4-dihydropyran-2-yl, coumal-5-yl, 5-methoxy4-oxopyran-2-yl, N-acetylpyrrolidin-2-yl, 5-oxo-tetrahydrofuran-2-yl, benzopyranone or (1-10C)alkyl [wherein (1-10C)alkyl is optionally substituted by hydroxy, cyano, halo, (1-4C)alkoxy, benzyloxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-6C)alkanoyl. (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-2-6C)alkanoylamino, (1-4C)alkylS(O)pNHxe2x80x94, (1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94, fluoro(1-4C)alkylS(O)pNHxe2x80x94, fluoro(1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C)alkylS(O)qxe2x80x94, phenylS(O)qxe2x80x94 (wherein the phenyl group is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0, 1 or 2];
or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted (1-10C)alkyl;
or R10 is of the formula R12Oxe2x80x94 wherein R12 is optionally substituted (1-6C)alkyl;
or R7 is of the formula RaOC(Rb)xe2x95x90CH(Cxe2x95x90O)xe2x80x94, RcC(xe2x95x90O)C(xe2x95x90O)xe2x80x94, Rd Nxe2x95x90C(Re)C(xe2x95x90O)xe2x80x94 or RfNHC(Rg)xe2x95x90CHC(xe2x95x90O)xe2x80x94 wherein Ra is (1-6C)alkyl, Rb is hydrogen or (1-6C)alkyl, or Ra and Rb together form a (3-4C)alkylene chain, Rc is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy, Rd is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, Re is hydrogen or (1-6C)alkyl, Rf is hydrogen, (1-6C)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl and Rg is hydrogen or (1-6C)alkyl;
or R7 is of the formula R14CH(R13) (CH2)mxe2x80x94 wherein m is 0 or 1, R13 is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R13 is not fluoro or hydroxy) and R14 is hydrogen or (1-4C)alkyl;
wherein AR is optionally substituted phenyl, optionally substituted phenyl(1-4C)alkyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted naphthyl or an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom;
wherein CY is a 4-, 5- or 6-membered cycloalkyl ring, a 5- or 6-membered cycloalkenyl ring, naphthoxy, thiophen-2-yl, indol-1-yl, indol-3-yl, pyrimidin-2-ylthio, 1,4-benzodioxan-6-yl, sulfolan-3-yl, pyridin-2-yl; wherein any of the afore-mentioned ring systems in CY may be optionally substituted by up to three substituents independently selected from halo, (1-4C)alkyl (including geminal disubstitution when CY is a cycloalkyl or cycloalkenyl ring), acyl, oxo and nitro-(1-4C)alkyl;
 greater than Xxe2x80x94Yxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 or  greater than CHCH2xe2x80x94;
and pharmaceutically-acceptable salts thereof.
In this specification a xe2x80x985- or 6-membered hetercarylxe2x80x99 and xe2x80x98heteroaryl (monocyclic) ringxe2x80x99 means a 5- or 6-membered aryl ring wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Particular examples of 5- or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
In this specification a xe2x80x985/6 or 6/6 bicyclic heteroaryl ring systemxe2x80x99 and xe2x80x98heteroaryl (bicyclic) ringxe2x80x99 means an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring, the bicyclic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Particular examples of 5/6 and 6/6 bicyclic ring systems are indole, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline. quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
In this specification a xe2x80x984-, 5- or 6-membered cycloalkyl ringxe2x80x99 means acyclobutyl, cyclopentyl or cyclohexyl ring; and a xe2x80x981- or 6-membered cycloalkenyl ringxe2x80x99 a means cycipentenyl or cyclohexenyl ring.
In this specification the term xe2x80x98alkylxe2x80x99 includes straight chained and branched structures. For example, (1-6C)alkyl includes propyl, isopropyl and tert-butyl. However, references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chained version only, and references to individual branched chain alkyl groups such as xe2x80x9cisopropylxe2x80x9d are specific for the branched chain version only. A similar convention applies to other radicals, for example halo(1-4C)alkyl includes 1-bromoethyl and 2-bromoethyl.
Particular optional substituents for alkyl, phenyl (and phenyl containing moieties) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings in R11, R12, Ri and AR include halo, (1-4C)alkyl, hydroxy, nitro, carbamoyl, (1-4C)alkylcarbamoyl, di-((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkylamino. di((1-4C)alkyl)amino, (1-4C)alkyl S(O)qxe2x80x94, (wherein q is 0, 1 or 2). carboxy, (1-4C)alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkanoyl, (1-4C)alkoxy, (1-4C)alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted by up to three substituents selected from halo, (1-4C)alkoxy or cyano), furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole. isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, hydroxy-(1-4C)alkyl, halo-(1-4C)alkyl, nitro(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanesulfonamido, aminosulfonyl, (1-4C)alkylaminosulfonyl and di-((1-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings in R11, Ri and AR may be mono- or disubstituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents.
Particular optional substituents for ring nitrogen atoms when Rxe2x88x92 is tetrazole, in heteroaryl groups in R11, R12, Rf and AR, and in the nitrogen-containing rings in CY, which can be substituted without becoming quaternised include (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkanoyl.
Examples of halo groups include fluoro, chloro and bromo; examples of (1-4C)alkyl, include methyl, ethyl, and propyl and isopropyl; examples of (1-6C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl and hexyl; examples of (1-10C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (1-4C)alkylamino include methylamino, ethylamino and propylamino; examples of di-((1-4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino and dipropylamino; examples of (1-4C)alkylS(O)qxe2x80x94 wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of (1-4C)alkylthio include methylthio and ethylthio; examples of (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkylaminocarbonyloxy include methylaminocarbonyloxy and ethylaminocarbonyloxy; examples of (1-4C)alkanoylamino-(1-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; examples of (1-6C)alkoxy-(1-6C)alkyl include methoxymethyl, ethoxymethyl and 2-methoxyethyl; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of (2-4C)alkanoyloxy include acetyloxy and propionyloxy; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxy include 2dimethylaminoethoxy and 2-diethylaminoethoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy and (1-6C)alkoxy(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido, acetamido and propionylamino; examples of (1-4C)alkoxycarbonylamino include methoxycarbonylamino and ethoxycarbonylamino; examples of N-(1-4C)alkyl-N-(1-6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N-methylpropionamido; examples of (1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of (1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94 wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoro(1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94 wherein p is 1 or 2 include trifluoromethylsulfinylmethylamino and trifluoromethylsulfonylmethylamino; examples of (1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl and ethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl include di-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include 2methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of 2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and 2-cyano-2-ethylethenyl; examples of 2-((1-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl; examples of benzyloxy(1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of phenyl(1-4C)alkyl include benzyl and phenethyl; examples of phenylS(O)q wherein q is 0, 1 or 2 are phenylthio, phenylsulfinyl and phenylsulfonyl respectively; examples of (1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of a (3-4C)alkylene chain are trimethylene or tetramethylene; examples of (2-4C)alkenyl include allyl and vinyl; examples of (2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoyl and (1-6C)alkanoyl include formyl, acetyl and propionyl; examples of hydroxyimino(1-4C)alkyl include hydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl; examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl, ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl; examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples of amino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of (1-4C)alkanesulfonamido include methanesulfonamido and ethanesulfonamido; examples of (1-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; and examples of di-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the formula (I).
An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
The compounds of the present invention have a chiral centre at the 5-position of the furanone ring. The 5(R) enantiomer of formula (IA) is the pharmaceutically active enantiomer: 
The present invention includes the pure 5(R) enantiomer or diastereoisomer and mixtures of the 5(R) and 5(S) enantiomers or diastereoisomers, for example a racemic mixture or equal mixtures of diastereoisomers. If a mixture of 5(R) and 5(S) is used, a larger amount (depending on the ratio of the enantiomers or diastereoisomers) will be required to achieve the same effects as the same weight of the 5(R) compound.
When xe2x80x94Axe2x80x94Bxe2x80x94 is of the formula  greater than CHCH2xe2x80x94 (i.e. when the ring is a 3,4-dihydrofuranone ring) there is also a chiral centre at the 3-position. The present invention relates to both the 3R and the 3S diastereoisomers.
Furthermore, some compounds of the formula (I) may have other chiral centres, and some compounds of the formula (I) may exist as one or more regioisomers. It is to be understood that the invention encompasses all such optical, diastereo- and regio-isomers that possess antibacterial activity.
The invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.
In a preferred aspect of the invention there is provided a compound of the formula (I) wherein:
R1 is hydroxy or of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl or xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2;
R2 and R3 are independently hydrogen or fluoro;
R4 and R5 are independently hydrogen or methyl;
 greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94,  greater than CHCH2 or  greater than C(OH)CH2xe2x80x94 ( greater than  represents two single bonds);
D is O, S, SO, SO2 or xe2x80x94NR7;
wherein R7 is hydrogen, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl or optionally substituted: phenyl, phenyl(1-4C)alkyl, 5- or 6-membered heteroaryl, naphthyl or 5/6 or 6/6 bicyclic heteroaryl ring system wherein the heteroaryl ring systems are joined to the nitrogen in NR7 by a ring carbon atom;
or R7 is of the formula R10COxe2x80x94 or R10SO2xe2x80x94
wherein R10 is amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, or (1-6C)alkyl [wherein (1-6C)alkyl is optionally substituted by hydroxy, cyano, (1-6C) alkanoyl, amino, (1-4C)alkylanino, di-(1-4C) alkylamino, (1-6C)alkanoylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O)p NHxe2x80x94, (1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94, phosphono, (1-4AC)alkoxy(hydroxy)phosphoryl, di1-4C)alkoxyphosphoryl, or (1-4C)alkylS(O)p wherein p is 1 or 2];
or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (1-6C)alkyl;
or R10 is of the formula R12Oxe2x80x94 wherein R12 is optionally substituted (1-6C)alkyl;
or R7 is of the formula RaOC(Rb)xe2x95x90CH(xe2x95x90O)xe2x80x94. RcC(xe2x95x90O)C(xe2x95x90O)xe2x80x94, RdN=C(Re)C(xe2x95x90O)xe2x80x94 or RfNHC(Rg)xe2x95x90CHC(xe2x95x90O)xe2x80x94 wherein Ra is (1-6C)alkyl, Rb is hydrogen or (1-6C)alkyl or Ra and Rb together form a (3-4C)alkylene chain, Rc is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylarnino, di-(1-4C)alkylamino, (1-6C) alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy, Rd is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, Re is hydrogen or (1-6C)alkyl, Rf is (1-6C)alkyl, phenyl or a 5- or 6-membered heteroaryl and Rg is hydrogen or (1-6C)alkyl;
or R7 is of the formula R14CH(R13)(CH2)mxe2x80x94 wherein m is 0 or 1, R13 is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy; (provided that when m is 0, R13 is not fluoro or hydroxy) and R14 is hydrogen or (1-4C)alkyl;
 greater than Xxe2x80x94Yxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 or  greater than CHCH2xe2x80x94;
and pharmaceutically-acceptable salts thereof.
In the above preferred aspect of the invention particular examples a xe2x80x985- or 6-membered heteroarylxe2x80x99 and xe2x80x98heteroaryl (monocyclic) ringxe2x80x99 are imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
Also in the above preferred aspect of the invention particular examples a xe2x80x985/6 or 6/6 bicyclic heteroaryl ring systemxe2x80x99 and xe2x80x98heteroaryl (bicyclic) ringxe2x80x99 are benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline and nanhthyridine.
Also in the above preferred aspect of the invention particular substituents for alkyl and phenyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings in R7, R11 or R12 include halo, (1-4C)alkyl, hydroxy, nitro, carbamoyl, (1-4C)alkylcarbamoyl, di((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkyl S(O)pxe2x80x94, (wherein p is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkanoyl, (1-4C)alkoxy (1-4C)alkanoylamino, benzoylamino, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, nitro(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanesulfonarnido and (1-4C)alkylaminosulfonyl.
In a further preferred aspect of the invention there is provided a compound of the formula (I) as defined in the above preferred aspect of the invention, wherein R10 when it is (1-6C)alkyl is additionally optionally substituted with (1-6C)alkoxy and benzyloxy; and pharmaceutically-acceptable salts thereof.
Particularly preferred compounds of the invention comprise a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, wherein the substituents A, B, D, X, Y and R1 to R5 and other optional substituents mentioned above have the values disclosed hereinbefore, or any of the following values:
(a) Preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl. Most preferably R1 is acetamido.
(b) Preferably one of R2 and R3 is hydrogen and the other is fluoro.
(c) Preferably  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 or  greater than CHCH2xe2x80x94.
(d) Preferably R4 and R5 are hydrogen.
(e) Preferably D is O, S or of the formula xe2x80x94NR7.
(f) Preferred substituents for phenyl and carbon atoms in heteroaryl (mono and bicyclic) ring systems in R7 and R11 include halo, (1-4C)alkyl, hydroxy, nitro, amino, cyano, (1-4C)alkyl S(O)pxe2x80x94 and (1-4C)alkoxy.
(g) Preferred optional substituents for (1-6C)alkyl in R11 are hydroxy, cyano, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkylS(O)p (wherein p is 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkoxy, piperazino or morpholino.
(h) Preferred optional substituents for (1-6C)alkyl in R12 are hydroxy, (1-4C)alkoxy, cyano, amino, (1-4C)alkylamino, di((1-2C)alkyl)amino, (1-4C)alkylS(O)p (wherein p is 1 or 2).
(i) Preferably the 5/6 or 6/6 bicyclic ring system in R7 is unsubstituted.
(j) Preferably 5- or 6- membered heteroaryl rings in R11 are unsubstituted.
(k) Preferably the 5- or 6-membered heteroaryl in R11 is pyridyl or imidazol-1-yl.
(l) Preferably R12 is (1-6C)alkyl. Most preferably R12 is methyl or tert-butyl.
(m) Preferably R13 is cyano or fluoro.
(n) Preferably R14 is hydrogen.
(o) Preferably R7 is hydrogen, benzyl, pyridyl, pyrimidyl, imidazolyl, triazolyl or of the formula R10COxe2x80x94.
(p) Preferably R10 is hydroxy(1-4C)alkyl, (1-4C)alkyl, dimethylamino(1-4C)alkyl, (1-4C)alkanoyloxy(1-4C)alkyl, benzyloxy(1-6C)alkyl, (1-5C)alkoxy or 2-cyanoethyl.
(q) More preferably R10 is hydroxymethyl, methyl, dimethylaminomethyl, acetoxymethyl, methoxy, tert-butoxy or 2-cyanoethyl. More preferably R7 is hydrogen, pyridyl, pyrimidyl, triazolyl, imidazolyl, benzyl, methoxycarbonyl, tert-butoxycarbonyl, hydroxyacetyl, dimethylaminoacetyl or methanesulfonyl.
(r) More preferably R10 is hydroxymethyl, methyl, benzyloxymethyl, acetoxymethyl, methoxy or tert-butoxy. More preferably R7 is hydrogen, pyridyl, pyrimidyl, triazolyl, imidazolyl, benzyl, methoxycarbonyl, tert-butoxycarbonyl, hydroxyacetyl. dimethylaminoacetyl or methanesulfonyl.
(s) Most preferably R10 is methyl, methoxy, tert-butoxy or hydroxymethyl. Most preferably R7 is hydrogen, methanesulfonyl, methoxycarbonyl, tert-butoxycarbonyl or hydroxyacetyl.
(t) Preferably XY is  greater than Cxe2x95x90CHxe2x80x94.
Therefore, especially preferred compounds are those defined in the above further preferred aspect of the invention wherein R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl;  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 or  greater than CHCH2xe2x80x94 and D is O, S or of the formula xe2x80x94NR7; and pharmaceutically-acceptable salts thereof.
Of the above especially preferred compounds, particular especially preferred compounds of the present invention are of the formula (I) wherein R1 is acetamido;  greater than Xxe2x80x94Yxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94; one of R2 and R3 is hydrogen and the other is fluoro;  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94; R4 and R5 are hydrogen; D is O, S or of the formula xe2x80x94NR7; R7 is hydrogen or of the formula R10COxe2x80x94; R10 is hydroxy(1-4C)alkyl, (1-4C)alkanoyloxy(1-4C)alkyl or (1-5C)alkoxy; and pharmaceutically-acceptable salts thereof.
Further particularly preferred compounds of the present invention are those as defined above as particular especially preferred compounds, but with R2 and R3 both hydrogen; and pharmaceutically-acceptable salts thereof.
Particular compounds of the present invention are:
5R-acetamidomethyl-3-(4-[1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)dihydrofuran-2(3H)-one;
5R-acetamidomethyl-3-(4-[1,2,5,6-tetrahydropyrid-4-yl]phenyl)dihydrofuran-2(3H)-one;
5R-acetamidomethyl-3-(4-[1-methoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-dihydrofuran-2(3H)-one;
5R-acetamidomethyl-3-(4-[1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-dihydrofuran-2(3H)-one;
5R-acetamidomethyl-3-(4-[1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-dihydrofuran-2(3H)-one;
5R-acetamidomethyl-3-(4-[1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
R-acetamidomethyl-3-(4-[1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-furan-2(5H)-one;
5R-acetamidomethyl-3(4-[1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-dimethylaminoacetoxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-methoxyethylcarbonyloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-hydroxyacetyloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-{4-pyridyl}-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-{2-pyridyl}-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-benzyloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[2,3-dihydropyran-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(4-[2,3-dihydrothiopyran-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(3-fluoro4-[2,3-dihydropyran-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(3-fluoro-4-[2,3dihydrothiopyran-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(3-fluoro-4-[1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(3-fluoro-4-[1,2,5,6-tetrahydropyrid-4-yl]phenyl)furan-2(5H)-one;
5R-acetamidomethyl-3-(3-fluoro-4-[1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid4-yl]phenyl)-furan-2(5H)-one;
5R-acetamidomethyl-3-(3-fluoro-4-[1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-furan-2(5H)-one;
or pharmaceutically-acceptable salts thereof.
In a further aspect the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt thereof. The compounds of formula (I) may be prepared by deprotecting a compound of formula (II): 
wherein R2-R5 and  greater than Xxe2x80x94Yxe2x80x94 are as hereinabove defined, R20 is R1 or protected R1,  greater than A1xe2x80x94B1xe2x80x94 is  greater than Axe2x80x94Bxe2x80x94 or protected  greater than C(OH)CH2xe2x80x94 and D1 is D in which functional groups are optionally protected; and thereafter, if necessary, forming a pharmaceutically-acceptable salt.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which xe2x80x9clowerxe2x80x9d signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing, 1-20 carbon atoms).
Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).
Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxy protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl) groups; and triaryl lower alkyl groups (eg triphenylmethyl).
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as o-nitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride.
Examples of protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (eg. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (eg. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (eg. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (eg. 2,4-di(methoxy)benzyl); and alkenyl (eg. allyl, but-1-enyl and substituted vinyl eg. 2-phenylvinyl).
Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with ceric ammonium nitrate. Finally alkenyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
For further examples of protecting groups see one of the many general texts on the subject, for example, xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora Green (publisher: John Wiley and Sons).
In another aspect of the present invention the compounds of the formulae (I) and (II) and pharmaceutically-acceptable salts thereof can be prepared:
a) by modifying a substituent in or introducing a substituent into another compound of the formula (I) or (II);
b) when R20 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl, wherein n is 1 or 2, by oxidising a compound of the formula (I) or (II) wherein n is 0 or, when n is 2 by oxidising a compound of the formula (I) or (II) wherein n is 1;
c) when R20 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl or xe2x80x94NHS(O)n(1-4C)alkyl, and  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90Cxe2x80x94,  greater than CHCH2xe2x80x94, or protected  greater than C(OH)CH2xe2x80x94 reacting a compound of the formula (III) with a compound of formula (IV): 
d) when R20 is hydroxy and  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94:
(i) by reacting a compound of the formula (V) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94,  greater than CHCH2xe2x80x94 or protected  greater than C(OH)CH2xe2x80x94 with a compound of formula (VI): 
or (ii) by reacting a compound of the formula (V) with a compound of the formula (VII): 
e) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94, by reacting a compound of the formula (VIII) with a compound of the formula (IX): 
f) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than CHCH2xe2x80x94 and  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94, by catalytic hydrogenation of a compound of the formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94 and  greater than Xxe2x80x94Y is  greater than CHCH2xe2x80x94;
g) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94 and  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94, by elimination of the elements of water, or HOCOR23or HOSO2R24 from a compound of the formula (X): 
h) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94 and  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHxe2x95x90CHxe2x80x94, by elimination of the elements of water, HOCOR23 or HOSO2R24 from a compound of the formula (X) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than C(OR25)xe2x80x94CH2xe2x80x94;
i) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94 and  greater than Xxe2x80x94Yxe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94 by elimination of PhSOH from a compound of the formula (XI); 
j) when D is NR7 and R7 is R10COxe2x80x94, R10S(O)nxe2x80x94 or R10CSxe2x80x94, by reacting a compound of the formula (XII) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94,  greater than CHCH2 or protected  greater than C(OH)CH2xe2x80x94, with a compound of the formula (XIII), (XIV) or (XV) respectively wherein n is 2: 
k) when R20 is of the formula xe2x80x94N(CO2R26)CO(1-4C)alkyl; from a compound of the formula (I) and (II) wherein R1 or R20 is hydroxy
wherein R2xe2x80x94R5 are as hereinabove defined, R19 is xe2x80x94C(xe2x95x90O)(1-4C)alkyl or xe2x80x94S(O)n(1-4C)alkyl, R21 is hydrogen or (1-6C)alkyl, R22 is a protecting group, R23 is (1-4C)alkyl, R24 is an optionally substituted phenyl group and R25 is hydrogen, (1-5C)alkanoyl or arylsulfonyl, R26 is (1-4C)alkyl or benzyl; n is 0, 1 or 2 unless otherwise stated; L1, L2 and L4a are leaving groups, L4b is a leaving group (for example (1-4C)alkoxy), L3 is an iodo or triflate leaving group, L4 is hydroxy or a leaving group and Z is a trialkyltin residue, a boronate acid or ester residue or a zinc monohalide and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pharmaceutically-acceptable salt.
Methods for converting substituents into other substituents are known in the art. For example an alkylthio group may be oxidised to an alkylsulfinyl or alkysulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a bromo group converted to an alkylthio group or a carbonyl group converted to a thiocarbonyl group (for example using Lawsson""s reagent).
Compounds of the formula (I) or (II) wherein R1 or R20 is xe2x80x94NHS(O)n(1-4C)alkyl can be prepared by oxidising a compound of the formula (I) or (II) with standard reagents known in the art for the oxidation of a thio group to a sulfinyl or sulfonyl group. For example, a thio group may be oxidised to a sulfinyl group with a peracid such as m-chloroperoxybenzoic acid and oxidising agents such as potassium permanganate will convert a thio group to a sulfonyl group. Compounds of the formula (I) or (II) wherein R1 or R20 is xe2x80x94NHS(1-4C)alkyl can be prepared by reacting compounds of the formula (III) with a reagent such as (1-4C)alkylSCl.
Standard reaction conditions for the acetylation of an amine group in a compound of the formula (III) or its conversion to a sulfonamido group are known in the art. For example, the amino group can be acetylated to give an acetamido group using the Schotten-Baumann procedure; reacting the compound of the formula (III) with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0xc2x0 to 60xc2x0 C., preferably between 0xc2x0 C. and ambient temperature. Preferably the acylation is carried out in situ following the catalytic hydrogenation of a compound of the formula (IIIA) (below), by performing the hydrogenation in the presence of acetic anhydride.
A compound of the formula (III) could, for example, be converted into a compound of the formula (I) or (II) wherein R1 or R is (1-4C)alkylSO2NHxe2x80x94 by reacting the compound of the formula (III) with a sulfonyl chloride. For example, by reacting the compound of the formula (III) with mesyl chloride in a mild base such as pyridine.
Alternatively, compounds of the formula (I) or (II) wherein R1 or R20 is (1-4C)alkylSO2NHxe2x80x94 or (1-4C)alkylSONHxe2x80x94 may be prepared by reacting a compound of the formula (III) with a compound of the formula (IV) wherein L1 is a phthalimido group.
The compound of the formula (IV) wherein L1 is phthalimido may be prepared by oxidising a compound of the formula (IVA): 
with standard oxidising agents known for the conversion of a thio group to a sulfinyl or sulfonyl group.
Compounds of the formula (IVA) can be prepared by reacting phthalimide with an alkylthiochloride ((1-4C)alkylSCl).
A compound of the formula (III) may be prepared by reducing a compound of the formula (IIIA): 
wherein R2xe2x80x94R5 are as hereinabove defined, and  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94,  greater than CHCH2xe2x80x94 or protected  greater than C(OH)CH2xe2x80x94.
Suitable reducing agents include triethylamine/hydrogen sulfide, triphenylphosphine and phosphite ester. More specifically a compound of the formula (IIIA) may be converted to a compound of the formula (III) by heating it in an aprotic solvent, such as 1,2-dimethoxyethane, in the presence of P(OMe)3 and subsequently in 6N aqueous hydrochloric acid. For further details on the reduction of azides to amines see U.S. Pat. No. 4,705,799. A compound of the formula (IIIA) may be reduced and converted to a compound of the formula (I) or (II) in situ using acetic anhydride in DMF.
A compound of the formula (IIIA) may be prepared by reacting a compound of the formula (IIIB): 
wherein R26 is mesyloxy or tosyloxy, with a source of azide. For example, by reacting (IIIB) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100xc2x0 C., normally in the region of 75xc2x0 C. 85xc2x0 C. A compound of the formula (IIIB) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R1 or R20 is hydroxy into a tosyloxy or mesyloxy group by standard methods known in the art. For example, by reacting the compound of the formula (I) or (II) with tosyl chloride or mesyl chloride in the presence of a mild base such as triethylamine or pyridine.
Alternatively, a compound of the formula (III) may be prepared using similar processes to those used hereinabove and hereinafter for the preparation of compounds of the formulae (I) and (II), wherein R20 is amino.
Compounds of the formulae (V) and (VI) are conveniently reacted together in the presence of a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide. The reaction is conveniently carried out in an inert solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), N,N1-dimethylpropyleneurea (DMPU) or NMP in a temperature range of xe2x88x9278xc2x0 C. to xe2x88x9250xc2x0 C. for the deprotonation. Suitable values for R21 include hydrogen, methyl and ethyl and suitable values for L2 include iodo and tosyloxy.
The intermediate product from the alkylation is cyclised to the final product of the formula (I) or (II) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94 and R1 or R20 is hydroxy, by heating it in aqueous acid, for example 5N hydrochloric acid, together with an organic co-solvent such as tetrahydrofuran.
Compounds of the formula (V) and (VII) are also conveniently reacted together in the presence of lithium diisopropylamide or lithium hexamethyldisilazide as above. The isolated product of this reaction may be cyclised to a compound of the formula (II) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94 and R20 is xe2x80x94OR22 by heating this intermediate product in an aqueous acid as the solvent. When R22 is benzyl or a similar protecting group and  greater than A1xe2x80x94B1xe2x80x94 is  greater than CHCH2xe2x80x94, xe2x80x94OR22 may be deprotected by hydrogenation using methods known in the art and when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94 by transfer hydrogenation, for example with ammonium formate.
A compound of the formula (V) is conveniently prepared by coupling a compound of the formula (VA) with a compound of the formula (IX): 
wherein R2xe2x80x94R5, R21L3, Z and D1 are as hereinabove defined.
The reaction between compounds of the formulae (VA) and (IX), wherein Z is trialkyltin and L3 is triflate is conveniently carried out in the presence of a palladium (0) catalyst such as Pd(PPh3)4 or Pd(dba)3 in a temperature range of 0-115xc2x0 C. Preferably the trialkyltin group is trimethyltin.
When Z is a boronate acid or ester, the reaction may be carried out under conditions known for the Suzuki reaction i.e. in the presence of a palladium (0) catalyst such as Pd(PPh3)4 or Pd(dba)3, in a water-miscible organic solvent such as dimethylformamide or 1,2-dimethoxyethane and in the presence of a mild base such as sodium acetate or sodium bicarbonate which is added in water. The reaction is then heated to up to 80xc2x0 C. Alternatively, silver oxide may be used in place of the base, in which case the reaction may be carried out at a lower temperature. Preferably L3 is iodo. Suitable boronate esters include lower alkyl and cyclic boronante esters.
The reaction between compounds of the formulae (VA) and (IX), wherein Z is a zinc monohalide is conveniently carried out in the presence of a palladium (0) catalyst such as Pd(PPh3)4 or Pd(dba)3, in an inert solvent such as tetrahydrofuran, toluene or acetonitrile, in a temperature range of ambient temperature to reflux.
A compound of the formula (VA) wherein Z is trimethylstannyl may be prepared by reacting a compound of the formula (VII) wherein Z is iodo or bromo, in an inert solvent with hexamethyldistannane in the presence of a palladium (0) catalyst, or by using methods similar to those described in Patent Application No. WO9413649. Compounds of the formula (VA) wherein Z is a cyclic boronate ester as in (VB): 
may be prepared from a compound of the formula (VA) wherein Z is iodo or bromo, by sequential treatment with a suitable Pd catalyst such as PdCl2(dppf), potassium acetate and the pinacol ester of diboron in a polar solvent such as DMSO (for example see J.Org.Chem., 1995, 60, 7508-7510).
A compound of the formula (VA) wherein Z is a zinc monohalide may be prepared by reacting the appropriate compound of the formula (VA) wherein Z is iodo or bromo with a reactive form of zinc, such as zinc dust activated with zinc-copper couple (Tet. Lett. 1988, 5013) or with zinc halide and lithium naphthalenealide (J.O.C. 56, 1445, (1991)).
A compound of the formula (IX) wherein D1 is R10CONxe2x80x94, S or O and L3 is triflate may be prepared by treating a compound of the formula (IXA) with lithium diisopropylamide in an inert solvent such as THF, at a low temperature, for example xe2x88x9278xc2x0 C., followed by N-phenyl triflamide (for example see methods described in Synthesis, 993-995 (1991)). 
Alternatively, a compound of the formula (IX) wherein L3 is iodo may be prepared by treating a hydrazone of a compound of the formula (IXA) with iodine in the presence of triethylamine (for example see methods detailed in Tet. Letts., 24, 1605-1608 (1983)).
Compounds of the formula (IX) and other intermediates in which D1 is NR7 and R7 is R14CH(R13)(CH2)mxe2x80x94 or optionally substituted: phenyl, phenyl(4C)alkyl, 5- or 6-membered heteroaryl, naphthyl or 5/6 or 6/6 bicyclic heteroaryl ring system may be prepared by elaboration of the piperidone ring from the appropriate alkyl-, aryl-, heteroaryl-, arylalkyl- or heteroarylalkyl-amine. The amine is reacted with ethyl acrylate to give the corresponding diethylarylimino-xcex2,xcex2xe2x80x2-dipropionate, which can be cyclised under Dieckmann conditions to give the corresponding piperidone xcex2-ketoester, followed by decarboxylation with heating in acid (see methods described in J.Chem.Soc., 5110-5118 (1962)).
Alternatively, a compound of the formula (IX) or other intermediate wherein R7 is heteroaryl may be prepared by reacting an appropriately substituted heterocycle containing a leaving group such as chloro, bromo or iodo with the appropriate 4-piperidone at an elevated temperature, in an inert solvent and optionally with an acid trapping agent.
The reaction between compounds of the formulae (VIII) and (IX) is conveniently carried out using similar methods to those described for the reaction between compounds of the formulae (VA) and (IX), except that Z is either trialkyltin or a boronate acid or ester. The compound of the formula (VIII) may be prepared from the corresponding compound in which Z is iodo or bromo using similar methods to those described for the preparation of a compound of the formula (VA).
A compound of the formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is of the formula  greater than CHCH2xe2x80x94 may be prepared from a compound of the formula (I) or (II) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94, by catalytic hydrogenation, using a suitable catalyst such as palladium-on-carbon in an appropriate inert or acidic solvent such as acetic acid.
The dehydration of a compound of the formula (X) to give a compound of formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 may be carried out using agents such as polyphosphoric acid, trifluoroacetic acid, trifluoroacetic anhydride, p-hydroxytosyl, sulfuric acid, thionyl chloride etc., in an inert solvent such as toluene, and at elevated temperatures. Suitable protection of the group R20 may be necessary as appropriate. A compound of the formula (X) wherein R20 is hydroxy, may be prepared by reacting a compound of the formula (VI) or (VII) with a compound of the formula (XA): 
using similar methods to those described for the reaction between compounds of the formulae (V) and (VI) or (VII). The hydroxy group R20 may then be converted to the amine as described in the preparation of a compound of the formula (III) and subsequently to the other values of R20.
A compound of the formula (XA) may be prepared by deprotecting a compound of the formula (XB): 
wherein R2xe2x80x94R5 and D1 are as hereinabove defined. The deprotection is conveniently carried out by refluxing it in aqueous mineral acid, such as 2N-3N hydrochloric acid.
A compound of the formula (XB) wherein R25 is (1-5C)alkanoyl or arylsulfonyl may be prepared by acylating or sulfonylating a compound of the formula (XB) wherein R25is hydrogen. For example, by reacting the latter compound with the appropriate acyl halide or sulfonyl chloride in the presence of a mild base such as pyridine.
A compound of the formula (XB) wherein R25is hydrogen, may be prepared by reacting the Grignard or zinc/lithium agent prepared from a compound of the formula (XC): 
wherein L5 is iodo or bromo with a compound of the formula (IXA). Typically a Grignard or lithium organometallic species can be prepared from a compound of the formula (XC) using standard methods known in the art. The formation of the organometallic species is normally carried out in an inert solvent such as ether or tetrahydrofuran. These solutions are cooled to low temperature, for example xe2x88x9250xc2x0 C. to xe2x88x9270xc2x0 C., and a solution of the compound of the formula (IXA) added, followed by warming to ambient temperature to complete the reaction. More preferably a zinc organometallic species is prepared from a compound of the formula (XC) by reacting the latter compound with activated zinc metal in an inert solvent (J.Org.Chem., 56, 1445 (1996)) or Tet. Lett., 5013 (1988) and reacting the resulting solution with a solution of the compound of the formula (IXA) in a temperature range of xe2x88x9230xc2x0 C. to 0xc2x0 C.
A compound of the formula (X) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than C(OR25)CH2xe2x80x94 may be prepared in a similar manner to a compound of the formula (X) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94 from an appropriate intermediate in which  greater than Xxe2x80x94Yxe2x80x94 is  greater than C(OR25)CH2xe2x80x94. The latter compound may be prepared by reacting the appropriate compound in which  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94 with oxyaziridine in the presence of a strong base such as hexamethyldisilazide, in an inert organic solvent such as tetrahydrofuran to give a compound in which  greater than Xxe2x80x94Yxe2x80x94 is  greater than C(OH)CH2xe2x80x94 and subsequently acylating or sulfonylating if necessary.
A compound of the formula (XI) is usually prepared as the PhSxe2x80x94 compound, elimination occurring on oxidation of the PhS group to PhSOxe2x80x94 giving a compound of the formula (I) or (II) wherein  greater than Xxe2x80x94Yxe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94. Standard oxidising agents are known in the art. One should select an oxidising agent which is capable of oxidising the xe2x80x94SPh group, but not other groups in the molecule. Preferred oxidising agents for this reaction include potassium peroxymonosulfate (oxone) and sodium periodate.
Compounds in which  greater than Xxe2x80x94Yxe2x80x94 is  greater than C(SPh)CH2xe2x80x94 are conveniently prepared by reacting the appropriate compound in which  greater than Xxe2x80x94Yxe2x80x94 is  greater than CHCH2xe2x80x94 with phenyl disulfide in the presence of a base such as potassium carbonate.
These procedures for converting  greater than Xxe2x80x94Yxe2x80x94 from  greater than CHCH2 into  greater than Cxe2x95x90CHxe2x80x94 are not only suitable for preparing compounds of the formula (I) or (II) but also for preparing other furanone intermediates in the preparation of compounds of the formula (I) or (II).
Where an optically active form of compounds of the formula (VI) or (VII) is used in previous steps, reduction of the  greater than Xxe2x80x94Yxe2x80x94 double bond will produce diastereoisomers which may be separated. Where a particular diastereoisomer is of choice, a chiral asymmetry-inducing catalyst for the reduction can be used.
Compounds of the formulae (XII) and (XIII) or (XIV) are reacted together under standard acylation or sulfonylation conditions. For example L4 may be chloro and the reaction may be performed in the presence of an organic base, such as pyridine or triethylamine, in a temperature range of 0xc2x0 C. to ambient temperature, in an inert organic solvent such as tetrahydrofuran or methylene chloride. Alternatively, the compound of the formula (XIII) may be replaced with acetic anhydride, in which case the reaction may be carried out in the presence of base such as sodium hydroxide under Schotten-Baumann conditions. When L4 is hydroxy, compounds of the formulae (XII) and (XIII) may be reacted together under conditions known in the art for amino acid coupling. For example, the reaction may be carried out in an inert organic solvent in the presence of a diimide-coupling agent such as dicyclohexylcarbodiimide (DCCI).
Compounds of the formula (I) or (II) wherein D or D1 is xe2x80x94NR7 and R7 is R14CH(R13)(CH2)mxe2x80x94 may be prepared by introducing the appropriate group onto the nitrogen in the compound of the formula (XII). When m is 0, the compound of the formula (XII) and R14CH(R13)L5 are conveniently reacted together under standard alkylation conditions. For example in an aprotic, solvent in the presence of an organic base such as triethylamine or pyridine, in a temperature range of 0-40xc2x0 C. Suitable values for L5 include halo, mesyl and tosyl. Preferably L5 is chloro.
When m is 1, compounds of the formulae (XII) and R14CH(R13)C(xe2x95x90O)H may be reacted together under conditions known for the formation of an iminium salt, which can be reduced in situ. For example, iminium salt formation and reduction in situ may be carried out in a water-miscible solvent such as ethanol or tetrahydrofuran, in the presence of a reducing agent such as sodium cyanoborohydride (NaCNBH3) under acidic conditions (Synthesis 135, 1975; Org. Prep. Proceed. Int. 11, 201, 1979). Alternatively the iminium salt may isolated and reduced with agents such as sodium borohydride or sodium cyanoborohydride to give the desired compound of the formula (I) or (II).
When m is 1 and R13 is not hydroxy, fluoro or (1-4C)alkoxy, a compound of the formula (I) or (II) may be prepared by reacting a compound of the formula (XII) with a compound of the formula R14C(R13)xe2x95x90CH2 under conditions suitable for the reaction known as the xe2x80x98Michael additionxe2x80x99. For example, in an inert aprotic solvent such as tetrahydrofuran, in the presence of a base, in a temperature range of ambient temperature to 100xc2x0 C.
When m is 1 and R3 is hydroxy, the compound of the formula (XII) may be reacted with an epoxy compound which is substituted on a ring carbon by R14. The reaction is conveniently carried out by heating the reagents together in a temperature range of 40-100xc2x0 C.
A compound of the formula (I) or (II) wherein D or D1 is SO or SO2 may be prepared by oxidising the corresponding compound in which D or D1 is S. Suitable oxidising agents for the conversion of D or D1 to SO include potassium metaperiodate and peracids such as metachloroperoxybenzoic acid. Stronger oxidising agents, such as oxone may be used to convert D or D1 to SO2.
A compound in which R7 is RfNHC(Rg)xe2x95x90CHC(xe2x95x90O)xe2x80x94 may be prepared by reacting the compound of the formula (XII) with a compound of the formula RgC(xe2x95x90O)CH2COOalkyl in an inert solvent such as toluene, at elevated temperature and either in the presence of 4-dimethylaminopyridine or 4-methylbenzenesulfonic acid to give a compound in which D is of the formula RgC(xe2x95x90O)CH2C(xe2x95x90O)xe2x80x94 and reacting the latter compound with a compound of the formula RfNH2 at elevated temperature in either toluene or acetic acid.
A compound in which R7 is 2-((1-4C)alkoxycarbonyl)ethenyl may be prepared by reacting a compound of the formula (XII) with 2-((1-4C)alkoxycarbonyl)ethynyl at elevated temperature in either an alcohol or in an inert organic solvent. The compound in which R7 is 2-((1-4C)alkoxycarbonyl)ethenyl may be converted to the corresponding compound in which R7 is 2-((1-4C)alkylaminocarbonyl)ethenyl by reacting the former compound with the appropriate amine in an inert organic solvent at elevated temperature.
A compound in which R7 is of the formula RaOC(Rb)xe2x95x90CH(xe2x95x90O)xe2x80x94 may be prepared by reacting a compound of the formula (XII) with a compound of the formula RbC(xe2x95x90O)CH2COOalkyl using similar conditions to those described for the reaction between a compound of the formula (XII) and a compound of the formula RgC(xe2x95x90O)CH2COOalkyl to form a compound in which R7 is of the formula RbC(xe2x95x90O)CH2COxe2x80x94 and reacting the latter compound with a halide of Ra, in an inert organic solvent such as THF, and in the presence of potassium carbonate.
A compound in which R7 is of the formula RcC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 may be prepared by reacting a compound of the formula (XII) with a compound of the formula RcC(xe2x95x90O)COCl in an organic solvent such as dichloromethane, in the presence of a mild base such as triethylamine and in a temperature range of 0-5xc2x0 C. It is preferable to form a compound in which Rc is an amino or substituted amino group by reacting a compound in which Rc is an alkoxy group with the appropriate amine.
A compound in which R7 is of the formula RdNxe2x95x90C(Re)C(xe2x95x90O)xe2x80x94 may be prepared from a compound in which R7 is RcC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 or from a similar compound. The imino group may be introduced into the latter group by reacting it with the appropriate amine in an inert sorganic solvent, at elevated temperature and in the presence of an acid catalyst.
The group R7 may be introduced into earlier intermediates in which D is NH using similar method to those described above. It is also possible to convert one R7 group into another R7 group as a final step in the preparation of a compound of the formula (I) or (II).
A compound of the formula (II) wherein R20 is of the formula xe2x80x94N(CO2R26)CO(1-4C)alkyl is conveniently prepared by reacting a compound of the formula (I) and (I) wherein R1 or R20 is hydroxy with an amide of the formula HN(CO2R26)CO(1-4C)alkyl under Mitsunobu conditions. For example, in the presence of tri-n-butylphosphine and 1,1xe2x80x2-(azodicarbonyl)dipiperidine in an organic solvent such as THF, and in the temperature range 0xc2x0 C.-60xc2x0 C., but preferably at ambient temperature. Details of analogous Mitsunobu reactions are contained in Tsunoda et al, Tet. Letts., 34, 1639, (1993). Amides of the formula HN(CO2R26)CO(1-4C)alkyl may be prepared by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.
When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material, or by resolution of a racemic form of the compound or intermediate using a standard procedure.
Similarly, when a pure regioisomer of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.
The invention also provides a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt thereof, in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example xcex2-lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness against methicillin-resistant staphylococci. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 mgkgxe2x88x921 to 20 mgkgxe2x88x921 of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
Antibacterial Activity
The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional tests.
The following results were obtained on a standard in vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot. Staphylococci were tested on agar, using an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. for 24 hoursxe2x80x94standard test conditions for the expression of methicillin resistance.
Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. in an atmosphere of 5% carbon dioxide for 48 hoursxe2x80x94blood is required for the growth of some of the test organisms.